{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T03:41:32Z","timestamp":1788493292364,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Chronic diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) remain a major source of morbidity, healthcare utilization, and limb loss, despite adherence to established standards of care protocols and the widespread availability of advanced wound technologies. Many advanced modalities only target isolated aspects of wound healing and fail to address the complex, interdependent pathophysiology of chronic wounds, particularly tissue hypoxia, edema, impaired microcirculation, and persistent inflammation. Cyclical Pressurized Topical Wound Oxygen (TWO2) therapy is a home-based, multimodal intervention that combines humidified topical oxygen delivery with cyclical non-contact compression to address these core drivers simultaneously. Methods: This review synthesizes mechanistic rationale and evidence from randomized controlled trials, long-term venous ulcer studies, and real-world comparative effectiveness analyses. Emphasis is placed on the large cohort study by Yellin et al., which directly compared TWO2 with other advanced modalities including negative pressure wound therapy (NPWT), skin substitutes, and growth factor therapies. Results: Across these studies, TWO2 therapy is consistently associated with improved healing durability, reduced recurrence, and substantial reductions in hospitalization and amputation rates compared with both standard care and advanced wound therapies. Conclusions: The convergence of randomized and real-world evidence supports TWO2 therapy as a clinically meaningful and mechanism-driven adjunctive treatment option for patients with chronic, high-risk lower-extremity wounds.<\/jats:p>","DOI":"10.3390\/jcm15124780","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T13:04:04Z","timestamp":1781874244000},"page":"4780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["TWO2 Therapy Demonstrates Clinically Meaningful Long-Term Outcomes Compared to Other Advanced Wound Care Modalities: Real-World Evidence Supported by Mechanistic and RCT Clinical Data"],"prefix":"10.3390","volume":"15","author":[{"given":"Anahita","family":"Dua","sequence":"first","affiliation":[{"name":"Division of Vascular and Endovascular Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naseer","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Manchester Vascular Centre, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyaandi R.","family":"Dove","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Clinical Nutrition and the Harold Schnitzer Diabetes Health Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4884-0151","authenticated-orcid":false,"given":"Matthew J.","family":"Regulski","sequence":"additional","affiliation":[{"name":"Ocean County Foot & Ankle Surgical Associates, P.C., Forked River, NJ 08753, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5248-3257","authenticated-orcid":false,"given":"Sara","family":"Rose-Sauld","sequence":"additional","affiliation":[{"name":"Division of Podiatry, Department of Orthopedic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew G.","family":"Garoufalis","sequence":"additional","affiliation":[{"name":"Department of Podiatric Medicine and Surgery, Western University of Health Sciences, Pomona, CA 91766, USA"},{"name":"Professional Foot Care Specialists, Chicago, IL 60632, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1089\/wound.2023.0150","article-title":"Human Wound and Its Burden: Updated 2022 Compendium of Estimates","volume":"12","author":"Sen","year":"2023","journal-title":"Adv. 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